November-December 2016, Volume 13, Issue 6
Indications for Therapeutic Plasma Exchange in Thrombotic Microangiopathies
Published on: October 28, 2016
What are the indications for therapeutic plasma exchange (TPE) in the setting of thrombotic microangiopathy (TMA)?
A 62 year old woman presents with a several-day history of progressive fatigue and shortness of breath. Initial laboratory results demonstrate anemia (hemoglobin, 6.6 g/dL) and severe thrombocytopenia (platelets, 8 × 109/L). The peripheral smear review shows schistocytes representing 8.6 percent of erythrocytes counted on manual differential. Apheresis medicine is consulted for initiation of TPE for probable diagnosis of thrombotic thrombocytopenic purpura (TTP).
TMAs are a diverse group of inherited and acquired disorders that have multiple etiologies resulting in a similar clinical presentation of microangiopathic hemolytic anemia (MAHA; defined as hemolytic anemia with RBC fragmentation) and thrombocytopenia. TMA has multiple mechanisms, including inherited or acquired deficiency of ADAMTS-13 (TTP), and hemolytic uremic syndrome (HUS) that is Shiga toxin-mediated (previously termed “typical HUS”), complement-mediated (inherited or acquired complement defects; previously termed “atypical HUS”), drug-associated, transplant-associated, and coagulation-mediated.1 Identifying the cause of the TMA is important because appropriate treatment varies.2
Other disorders may present with MAHA and thrombocytopenia, including, but not limited to, autoimmune disorders (systemic lupus erythematosus [SLE] and antiphospholipid antibody syndrome), systemic infections, systemic malignancy, malignant hypertension, and, in the setting of pregnancy, pre-eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).3 Clinical history and additional laboratory testing can help narrow the differential diagnosis.1
Guidelines for the Use of Therapeutic Plasma Exchange
The American Society for Apheresis (ASFA) regularly publishes guidelines outlining evidence-based recommendations for the use of therapeutic apheresis.4 These guidelines are updated every three years by ASFA writing committee members using a uniform approach to review existing literature and assign category recommendations based on current evidence (category I, first-line therapy; category II, second-line therapy; category III, role of apheresis is unknown; and category IV, not indicated). The strength of the recommendation reflects the methodological quality of current evidence using the GRADE system.5,6 Each disease or condition is summarized in a single-page fact sheet which includes the recommendation for apheresis for each indication (i.e., specific situation encountered in the disease) and apheresis modality (i.e., TPE vs. immunoadsorption), along with a comprehensive and succinct summary of the disease, current management, and rationale for therapeutic apheresis.
Table 1. Category and Grade Recommendations for TPE Category I Indications
|Acute inflammatory demyelinating polyradiculoneuropathy/
|Acute liver failure||TPE-high volume||I||1A|
|ANCA-associated rapidly progressive glomerulonephritis
(granulomatosis with polyangiitis; and microscopic polyangiitis)||Dialysis dependence|
|Anti-glomerular basement membrane disease (Goodpasture’s
|Chronic inflammatory demyelinating polyradiculoneuropathy|| ||I||1B|
|Focal segmental glomerulosclerosis||Recurrent in transplanted kidney||I||1B|
|Hyperviscosity in monoclonal gammopathies||Symptomatic|
Prophylaxis for rituximab
|Liver transplantation||Desensitization, ABO incompatible LD||I||1C|
|N-methyl D-aspartate receptor antibody encephalitis*|| ||I||1C|
|Paraproteinemic demyelinating neuropathies/chronic acquired
|Progressive multifocal leukoenchephalopathy associated with
|Renal transplantation, ABO compatible||Antibody mediated rejection|
|Renal transplantation, ABO incompatible||Desensitization, LD||I||1B|
|Thrombotic microangiopathy, complement mediated**||Factor H autoantibodies||I||2C|
|Thrombotic microangiopathy, drug associated**||Ticlopidine||I||2B|
|Thrombotic thrombocytopenic purpura**|| ||I||1A|
Abbreviations: ANCA, antineutrophil cytoplasmic antibody; DAH, diffuse alveolar hemorrhage; LD, living donor; TPE, therapeutic plasma exchange.
*New fact sheets in 2016 edition
**TMA-specific fact sheets
Disease names, category recommendations, and indications for some diseases have been modified with each guideline update to reflect current recommendations based on improved understanding of disease mechanisms and emergence of new evidence. Significant changes in the 2016 update include 14 new fact sheets. There are currently 18 category I indications for TPE, including two new fact sheets in the 2016 edition (N-methyl-D-aspartate receptor antibody encephalitis and progressive multifocal leukoencephalopathy associated with natalizumab; Table 1).4
Table 2. Defining and Categorizing TMAs Over Time
|2007 Indication||Category||2010 Indication||Category||2013 Indication||Category||2016 Indication||Category|
|HUS; TMA; TAM||HUS||HUS, atypical||TMA, coagulation-mediated|
|Idiopathic HUS||III||Atypical HUS due to complement factor gene mutations||III||Complement gene mutations||II||THBD mutation||III|
|Other||III||Atypical HUS due to autoantibody to Factor H||I||Factor H antibodies||I||TMA, complement-mediated|
|TAM||III||Diarrhea-associated HUS or typical HUS||IV||MCP mutations||IV||Complement factor gene mutations||III|
|Diarrhea-associated pediatric||IV||TMA, drug-associated||HUS, infection-associated||Factor H autoantibodies||I|
|Ticlopidine/Clopidogrel||I||Shiga toxin-associated||IV||MCP mutations||III|
|Cyclosporine/Tacrolimus||III||S. pneumoniae associated||III||TMA, drug-associated|
|TMA, hematopoietic stem cell transplant-associated||III||Clopidogrel||III||Calcineurin inhibitors||III|
|Quinine||IV||TMA, hematopoietic stem cell transplantation-associated||III|
|TMA, hematopoietic stem cell transplant-associated||TMA, Shiga toxin-mediated|
|Refractory||III||Severe neurological symptoms||III|
|Absence of severe neurological symptoms||IV|
Abbreviations: HUS, hemolytic uremic syndrome; TAM, transplant-associated microangiopathy; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.
The evolution of guidelines for the use of TPE in the setting of TMA (previously termed TTP/HUS) are summarized in Table 2.4 While TTP has remained a standalone fact sheet with a category I recommendation for TPE in the last four publications, other TMAs that were initially combined in a single fact sheet in the 2007 edition are now described in five separate fact sheets in the 2016 edition. Additional changes to TMA-specific fact sheets include a new fact sheet for coagulation-mediated TMA (THBD mutation, category III); an update to complement mediated TMA recommendations (complement gene mutations changed from category II to III; MCP mutations changed from category IV to III); and expansion of Shiga toxin–mediated TMA (previously referred to as HUS, infection-associated, Shiga toxin–associated; category IV) indications to include severe neurological symptoms (category III) and absence of severe neurological symptoms (category IV). A new fact sheet for HELLP syndrome, a mimicker of TTP in pregnant women, has also been added (category III).7
Category I Indications for TPE in TMA
In the 2016 guidelines, there are three category I indications for TPE in the setting of TMA (TTP, complement-mediated TMA due to Factor H autoantibodies, and drug-associated TMA due to ticlopidine; Table 1). These disorders share the feature of antibody production resulting in endothelial damage (TTP and Factor H autoantibodies) and/or deficiency (typically < 10%) of ADAMTS-13 (TTP and ticlopidine-associated TMA) or complement regulators (Factor H autoantibodies). TPE in these disorders removes the autoantibody and replaces ADAMTS-13 protein or complement regulators by using plasma as the replacement fluid.
These disorders are in contrast to those that have different mechanisms that may result in similar clinical presentations but for which TPE is not recommended owing to evidence that it is ineffective or harmful (category IV). These include gemcitabine or quinine-associated TMA or Shiga toxin–mediated TMA in the absence of severe neurological symptoms. Gemcitabine-associated TMA is thought to be caused by drug-associated damage to the renal microvasculature, and existing evidence does not demonstrate any survival benefit when TPE is used for this disorder.8 Although quinine-associated TMA seems to be antibody mediated (quinine-dependent antibodies target platelet glycoproteins and other cells), ADAMTS-13 levels are normal, and TPE is relatively ineffective at antibody removal.9 The mechanism for Shiga toxin–mediated TMA involves damage to the vascular endothelium and activation of the alternative complement pathway. Current evidence shows no benefit of TPE in patients with Shiga toxin–mediated TMA except perhaps in those with severe neurologic symptoms (category III).10,11
Our Clinical Case
In our case, laboratory evidence of MAHA and thrombocytopenia in the absence of any other causes of TMA based on clinical history and laboratory testing was sufficient for prompt initiation of TPE for suspected TTP.3 Prior to TPE initiation, an ADAMTS-13 level was obtained, and intravenous steroids were started. After urgent venous catheter placement, we performed a 1.0-volume TPE using plasma as the replacement fluid. The patient was without any signs of renal or neurologic involvement at the time. However, by the next day, she was noted to be febrile overnight and having word-finding difficulties that progressed to inability to speak throughout the course of the second hospital day. This prompted us to escalate the treatment to twice-daily TPE using cryo-poor plasma.3
The platelet count increased to 14 × 109/L by hospital day 3, and her mental status returned to baseline. We continued to perform daily 1.5-volume TPE. ADAMTS-13 levels returned on hospital day 4 at less than 5 percent, with an inhibitor titer of 2.3. Platelet counts improved initially (8 à 14 à 35 à 46 × 109/L) but then began to decrease on hospital day 5 (46 à 38 à 37 à 10 × 109/L). Rituximab was started on hospital day 7 because of a continued decline in the platelet count and worsening lactate dehydrogenase level (LDH).3 Renal function began to worsen on hospital day 9, and twice-daily 1.0-volume TPE was re-initiated. Platelet counts remained in the single digits (6 to 8 × 109/L) for four consecutive days. A repeat ADAMTS-13 was drawn on hospital day 12 and demonstrated ADAMTS-13 levels lower than 5 percent, with an increase in inhibitor titer to 2.8. Due to her refractory disease, bortezomib was added to her treatment regimen on hospital day 12.12 Platelet counts began to slowly increase on hospital day 13, and she was transitioned to daily 1.5-volume TPE. Her platelet counts are currently recovering, but remain lower than 150 × 109/L, along with normalization of the LDH level and improvement in her renal function. She still is receiving daily TPE on hospital day 20.
A diverse group of disorders can present with TMA. In the case of TTP, prompt initiation of TPE can be life-saving. However, treatments vary depending on the mechanism causing the TMA, and TPE is not effective for all disorders. Recommendations for the use of TPE in TMA and other diseases are available in the ASFA guidelines and are updated every three years to reflect changes in understanding of disease mechanisms and review of existing evidence supporting the use of TPE for TMA indications.
Go RS, Winters JL, Leung N, et al. Thrombotic microangiopathy care pathway: a consensus statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proc. 2016;91:1189-1211.
Mehmood T, Taylor M, Winters JL. Management of thrombotic microangiopathic hemolytic anemias with therapeutic plasma exchange: when it works and when it does not. Hematol Oncol Clin North Am. 2016;30:679-694.
George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060-4069.
Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. 2016;31:149-162.
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest. 2006;129:174-181.
Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926.
Pham HP, Schwartz J. New apheresis indications in hematological disorders. Curr Opin Hematol. 2016. [Epub ahead of print].
Gore EM, Jones BS, Marques MB. Is therapeutic plasma exchange indicated for patients with gemcitabine-induced hemolytic uremic syndrome?. J Clin Apher. 2009;24:209-214.
Park YA, Hay SN, King KE, et al. Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy. J Clin Apher. 2009;24:115-119.
Menne J, Nitschke M, Stingele R, et al. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ. 2012;345:e4565.
Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2010;5:1218-1228.
Patriquin CJ, Thomas MR, Dutt T, et al. Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura. Br J Haematol. 2016;173:779-785.
Conflict of Interests
Drs. Dunbar and Shaz indicated no relevant conflicts of interest.
back to top